Arsenic is a well-documented human carcinogen. Our goal is to address the central hypothesis that MAP kinases, p90 S6 kinases, and histone H3 are mediators of arsenic-induced signal transduction and cell transformation. The Specific Aims are: Specific Aim 1, to determine whether arsenic-induced p38 kinase is required for arsenic-induced cell transformation; Specific Aim 2, to determine the role of c-Jun N-terminal kinases (JNKs) in arsenic-induced cell transformation and apoptosis; Specific Aim 3, to determine whether activation of p90 S6 kinase/MAPKAP-K1 (p90RSK) is involved in arsenic-induced signal transduction and cell transformation; and Specific Aim 4, to determine the role of p38 kinase, JNKs, and p90RSK in arsenic-induced phosphorylation of histone H3 and the role of phosphorylation of histone H3 in cell transformation. The strategy for Specific Aim 1 is to use p38 kinase inhibitors or dominant negative mutants or siRNA to inhibit p38 kinase activation. For Specific Aim 2, we will (1) test whether inactivation of JNK phosphorylation is required for development of resistant phenotype to arsenic; (2) test whether inhibition of JNK phosphorylation/activation will cause inhibition of arsenite-induced cell transformation or apoptosis; (3) test whether introduction of an active JNK mutant into arsenic resistant cells will cause the rescue of the apoptosis-resistant phenotype. For Specific Aim 3, we will inhibit p90RSK using cell lines expressing a dominant negative mutant or siRNA of p90RSK and cell lines which are deficient in p90RSK. For Specific Aim 4, we will (1) block the activation of JNK, p38, and p90RSK by specific inhibitors, dominant negative mutants, siRNA, or gene knockout cell lines; (2) use cell lines expressing siRNA of histone H3, dominant negative mutants (histone H3 S10 mutated to A10, H3 S28 mutated to A28) and histone H3 wild-type to study the role of histone H3 in arsenic-induced cell transformation. Such knowledge will facilitate the design of more effective and specific strategies with fewer side effects for chemoprevention of arsenic-induced cancer.